Technical Field
This disclosure is generally related to a synthetic process for preparing 2-((2-ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl 5-tetradecyloxy)furan-2-carboxylate, a prodrug of a fatty acid mimetic.
Background
Fatty acid synthesis starts with the carboxylation of acetyl CoA to malonyl CoA. This irreversible reaction is the committed step in fatty acid synthesis. The synthesis of malonyl CoA is catalyzed by acetyl CoA carboxylase (ACC) (See, Brownsey, R. W. et al., “Regulation of acetyl-CoA carboxylase”, Biochem Soc. Trans. (2006) 34: 223-227).
Inhibition of ACC can be effective in diminishing fatty acid synthesis. Long-chain (16-20 carbons) fatty acid acyl-CoA thioesters have been found to be potent physiological end-product inhibitors of mammalian ACC.
TOFA (5-(tetradecyloxy)-2-furoic acid) is a known fatty acid mimetic, which can be converted intracellularly to its acyl-CoA thioester, thus inhibiting ACC activity with a mechanism similar to long chain fatty acid acyl-CoA thioesters. See, McCune, S. A. et al., J. Biol. Chem. (1979), Vol. 254, No. 20, pp. 10095-10101.
TOFA has the following structure:

TOFA has been shown to reduce plasma triglyceride levels in both rats and monkeys. See, e.g., Parker, R. A. et al., J. Med. Chem. (1977), Vol. 20, pp. 781-791. It has also been known to inhibit hepatic fatty acid synthesis. See, e.g., Ribereau-Gayon, G., FEBS Lett. (1976), Vol. 62, No. 309-312; Panek, E. et al., Lipids (1977), Vol. 12, pp. 814-818; Kariya, T. et al., Biochem. Biophys. Res. Commun. (1978), Vol. 80, pp. 1022-1024; and Harris, R. A. et al., Hormones and Energy Metabolism (Klachko, D. M. et al., eds.), Vol. III, pp. 17-42. TOFA is further known to inhibit sebaceous gland disorders by lowering sebum production. See, e.g., U.S. Published Patent No. 2010/0204317, and German Patent No. 40 33 563.
TOFA has poor bioavailability through the skin. On the other hand, certain TOFA prodrugs have been found to be particularly effective against a range of dermatological disorders including acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin. See U.S. Pat. No. 8,884,034, in the name of Dermira (Canada) Inc.
One such TOFA prodrug is 2-((2-ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl 5-tetradecyloxy)furan-2-carboxylate, having the following structure:

There is a need to modify the synthetic approach to produce TOFA prodrugs at improved yields and scalability.